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Abstract

Abstract This article reviews our work on the effects of different classes of antihypertensive agents on the hemodynamic alterations in essential human hypertension. Short-term studies were done during cardiac catheterization in young normotensive subjects (mean age, 33 years; range, 19 to 40) and several different age-matched (range, 25 to 53 years) groups of patients with essential hypertension. Aortic impedance, resistance, wave reflections, and compliance were calculated from high-fidelity recordings of ascending aortic pressure and flow signals during baseline and after nitroprusside, propranolol followed by phentolamine, phentolamine, captopril, and nifedipine, respectively, at doses sufficient to normalize blood pressure in each hypertensive group. Propranolol exacerbated all the hemodynamic parameters; these effects were only partially overcome by phentolamine. Among the other agents only phentolamine did not completely normalize compliance, and only captopril did not completely normalize wave reflections. The long-term study was a randomized, double-blind comparison of fosinopril and atenolol in 79 normotensive subjects and 79 essential hypertensive patients. Baseline 24-hour ambulatory blood pressures and carotid artery tonometry to index wave reflections were performed in all subjects and in hypertensive patients after 8 weeks of therapy. Both fosinopril and atenolol normalized blood pressure and lowered the elevated augmentation index, but fosinopril had a significantly larger effect than atenolol. Both short- and long-term β-blockade did not have as beneficial an effect as the other agents. Thus, the differing hemodynamic effects of the various classes of antihypertensive agents might be a consideration in the choice of therapy.

Compared with age-matched normotensive control subjects, humans with essential hypertension have distinctly altered hemodynamics, including increased arterial resistance, wave reflections, and impedance and decreased compliance.12345 Dysfunction of several systems has been identified in essential hypertension, including alterations in autonomic nervous system activity,678910 abnormal levels of circulating and tissue angiotensin,111213141516 altered vascular endothelial function,1718 and abnormal calcium handling by vascular smooth muscle cells.1920212223 Consequently, antihypertensive agents specifically aimed at one or more of these systems have been developed. Since the various classes of antihypertensive agents have different mechanisms of action on the arterial system, one might expect them to affect the altered hemodynamics differently after both short- and long-term administration.

Detailed characterization of many aspects of hemodynamic function, such as arterial impedance and wave reflection, currently requires invasive measurement of high-fidelity pressures and flows during cardiac catheterization.24252627282930 Consequently, such measurements are restricted to a few selected patients and are suitable for examination of only the short-term effects of drugs. Some recently described noninvasive techniques such as Doppler ultrasound3132 and arterial applanation tonometry333435 are now able to provide some corroborating measurements of a few aspects of hemodynamics, such as regional compliance and wave reflection, respectively. Hence, these techniques allow for the examination of long-term effects of antihypertensive agents.

Using invasive techniques we examined the short-term hemodynamic effects of several different classes of antihypertensive agents (smooth muscle dilator, β-blocker, α-blocker, angiotensin-converting enzyme [ACE] inhibitor, and calcium channel blocker) in several different groups of patients with essential hypertension. We also used noninvasive techniques in a randomized double-blind comparison of a β-blocker and ACE inhibitor. This review summarizes our results.

Methods

Short-term Studies

Patients and Study Protocol

Normotensive data were obtained from patients (mean age, 32.6 years; range, 19 to 40) undergoing diagnostic cardiac catheterization for other reasons (usually electrophysiological studies). Five different age-matched (mean age, 34.1 years; range, 25 to 53) groups of hypertensive patients were studied. During multiple clinic visits and after hospital bed rest, all these hypertensive patients consistently had sphygmomanometric blood pressure (BP) readings greater than 140/90 mm Hg. Secondary causes of hypertension were ruled out in every patient. Those entered into the study either had never been treated for hypertension or had their antihypertensive medications discontinued for at least 2 weeks before study. None of the normotensive subjects or hypertensive patients had coronary artery disease, valvular heart disease, or physical findings of peripheral or carotid artery disease. All patients gave informed consent for the study according to institutional guidelines. A two-dimensional echocardiogram for assessment of aortic root diameter was performed in every patient. Since we have previously shown that aortic root cross-sectional areas did not vary by more than 0.2 cm2 when BP values were lowered over the same range as in these patients,1 we used this initial estimate of aortic root area to convert the flow velocity (see below) to volume flow.

All patients were premedicated with chlorpheniramine maleate (5 mg IM). At the time of catheterization a catheter (model VPC 673-D or SVPC 684-D, Millar Instruments) containing a micromanometer and electromagnetic flow velocity sensor was advanced into the aortic root through a femoral artery sheath. Baseline pressures, flows, and electrocardiograms were recorded on analog tape for later off-line analysis. For each group a dose of the selected antihypertensive agent then was administered according to the following procedures: (1) For the nitroprusside group1 intravenous nitroprusside was begun at a dose of 0.25 mcg/kg per minute and doubled every 3 minutes until BP fell into the normal range. (2) For the adrenergic blockade groups36 intravenous propranolol was given at a rate of 1 mg/min until a total dose of 0.15 mg/kg was administered. Recordings were made several minutes after completion of the infusion. Combined α- and β-blockade then was produced by administration of intravenous phentolamine beginning at a rate of 1 mg/min. The dose was increased by 1 mg/min every 3 minutes until both systolic and diastolic pressures fell into the normal range. Recordings were made for 3 to 5 minutes on completion of the infusion. (3) For the α-blockade only group (unpublished data) intravenous phentolamine was given according to the same protocol as above. (4) For the captopril group37 2 mg was first given intravenously over 1 minute, and recordings were made after 10 minutes. If either systolic or diastolic pressure was still elevated, another 4 mg was given. If after 10 minutes pressures were still elevated, 8 mg was given. The average dose used was 11 mg (range, 6 to 14 mg). (5) For the nifedipine group38 10 or 20 mg of sublingual nifedipine was given depending on whether the diastolic pressure was less or greater than 105 mm Hg, respectively. After 15 minutes if either systolic or diastolic pressure was still elevated, another 10 mg was given sublingually, and recordings were made after another 15 minutes. The average maximum dose was 24.2 mg (range, 10 to 30 mg).

Data Analysis

The calibration and data analysis methods have been reported in detail previously.1 In brief, the pressure and flow signals were resolved into their Fourier harmonics. The impedance modulus and phase angle for each harmonic were calculated as the ratio of the pressure and flow modulus and the flow minus the pressure angle, respectively. The pressure signal was then decomposed into its forward (Pf) and backward (Pb) components,39 from which an index of wave reflection (Pb/Pf) was calculated. For comparison with the long-term studies, another index of the effect of wave reflections, the augmentation index (AI), was calculated from the ascending aortic pressure signals with the use of previously described definitions.26404142 Finally, an estimate of arterial compliance was obtained (assuming a three-element Windkessel model for the arterial system) with the use of the pressure-area method.3043 The results reported herein are for the compliance extrapolated to zero pressure (C0). Because this method explicitly accounts for the pressure dependence of compliance, calculations of compliance at the prevailing levels of systolic, diastolic, and mean pressures can be obtained simply by multiplying C0 by the parameter ebP, where b is a constant (taken here to be −0.001) and P is the pressure. The data reported here represent the averages from a minimum of 6 (usually closer to 15) beats.

Statistical comparisons were performed using unpaired t tests and repeated measures ANOVA with the Bonferroni correction for multiple comparisons as appropriate. Statistical significance was assumed at a value of P=.05.

Long-term Study

Study Subjects

From a mass public health screening of residents older than 30 years in a region of Taiwan and on Quemoy Island, we identified 79 normotensive subjects (BP <140/90 mm Hg) and 79 hypertensive patients. From a complete history, physical examination, and routine blood tests, individuals with secondary hypertension, malignant hypertension, unstable angina, myocardial infarction within the preceding 6 months, liver or renal function abnormalities, or contraindications for β-blockers or ACE inhibitors were excluded. After giving informed consent the hypertensive patients stopped previous antihypertensive drugs and received placebos for 2 weeks. Only those with an average of the three sitting diastolic BP values between 95 and 110 mm Hg after 2 weeks of placebo treatment were entered into the study. The study was a double-blind design with patients randomly assigned to receive 10 mg fosinopril daily (41 patients) or 50 mg atenolol daily (38 patients). The dosage was doubled if the average sitting diastolic BP was above 90 mm Hg after 2 weeks of active treatment. Dihydrochlorothiazide (25 mg daily) was then added if the averaged diastolic BP was still above 90 mm Hg after 4 weeks of active treatment. This was required in 29 of the 41 fosinopril patients and 23 of the 38 atenolol patients. The medication was continued for another 4 weeks. Ambulatory BP, carotid tonometry, and echocardiography (see below) were performed at the first visit and after 8 weeks of treatment. The data reported are for the entire hypertensive group as well as for the subgroup that did not receive diuretic therapy. All of these same measurements were made in the normotensive group at the time of the visit to the public health clinic.

Ambulatory BP

To obtain a more representative assessment of BP profiles than available from single clinic visits, we recorded baseline 24-hour ambulatory BP using a SpaceLabs 90207 recorder44 in all subjects as well as 24-hour BP after completion of drug treatment in the hypertensive patients. The recorder was programmed to deflate in steps of 4 mm Hg at 20-minute intervals during the daytime (7 am to 10 pm) and at 60-minute intervals during the nighttime (11 pm to 6 am). Usually, 50 to 60 readings throughout 24 hours could be obtained in most patients. Patients were advised to work as usual during monitoring but to minimize movement of the arm in which BP was being measured. The 24-hour readings were not edited manually, but the software from the manufacturer stipulates that records with less than 80% successful measurements be excluded. None of our subjects were excluded from analysis for failing to meet this criterion. The mean 24-hour systolic BP, diastolic BP, and heart rate, as well as mean hourly BP and heart rate, were obtained directly from the report generated by a computer software package after the data were retrieved from the recorder through an interface.

Carotid Tonometry

The arterial pressure wave contour with the subject in the supine position was obtained noninvasively from the right common carotid artery with a hand-held 7-mm-diameter pencil-type probe incorporating a micromanometer (Millar Instruments).333435 The carotid waveform was digitized at a rate of 250 Hz and stored on an IBM-compatible microcomputer for off-line analysis. The digitized signals were analyzed with the use of custom software written in our laboratory. Two to 10 consecutive beats were signal averaged. Premature beats and beats immediately after premature beats were excluded. From this signal-averaged beat we calculated the AI as previously described.26404142 The interobserver variability of the carotid AI has been determined from another 62 patients. The observations of the two observers were consistent and highly correlated with a regression equation of y=1.06x+0.45 (SEE=0.04, R=.964, P<.001). The intraclass correlation coefficient was .95, with a 95% confidence interval of .88 to .98. There was a significant but small mean difference between the two independent observers’ values of −0.15 (=.002). The long-term AI data reported herein are those of one observer (C.-H.C.).

Statistical Analysis

All variables are expressed as mean±SD. The within-groups and between-groups comparisons of BP and AI were performed using two-way ANOVA. An identical analysis was performed for the subgroup of subjects who did not receive diuretic therapy. Statistical significance was considered to be at a value of P=.05 although all probability values less than .10 are listed.

Results

Short-term Studies

The results for the short-term studies are summarized in Figs 1 through 7⇓⇓⇓⇓⇓⇓⇓, which show the heart rate, BP, arterial resistance, first harmonic of the impedance modulus, wave reflection index, aortic AI, and compliance at extrapolated zero pressure responses, respectively, for the normotensive subjects and each group of hypertensive patients. Each of the drugs normalized BP. Each drug with the exception of propranolol reduced resistance and the impedance modulus to normal. This deleterious effect of β-blockade could be only partially overcome by α-blockade. β-Blockade had a similar deleterious effect on both the wave reflection index and AI as well as on compliance. Only nitroprusside and the calcium channel antagonist were able to completely normalize all the hemodynamic parameters. Phentolamine did not completely normalize compliance, and captopril did not completely normalize wave reflections.

Bar graphs show systolic and diastolic pressures in normotensive subjects and short-term responses to various classes of antihypertensive agents. Definitions are as in Fig 1⇑ legend. Each drug effect compared with baseline or intervening drug (combined α- and β-blockade) values is statistically significant.

Bar graph shows index of wave reflections (ratio of backward [Pb] to forward [Pf] component of pressure wave) in normotensive subjects and short-term responses to various classes of antihypertensive agents. Definitions are as in Fig 1⇑ legend.

Bar graph shows arterial compliance extrapolated to zero pressure in normotensive subjects and short-term responses to various classes of antihypertensive agents. Definitions are as in Fig 1⇑ legend. Each drug effect compared with baseline or intervening drug (combined α- and β-blockade) values is statistically significant.

Long-term Study

The results of the long-term study are summarized in Figs 8 through 10⇓⇓⇓, which illustrate 24-hour heart rate and BP and the carotid AI responses, respectively. Results for individuals taking the two drugs along with the diuretic as well as those for the subgroup taking only the drugs are shown. In general, the results for the subgroups and the whole groups were consonant. As expected, atenolol decreased heart rate compared with normotensive control subjects and the fosinopril group. Both atenolol and fosinopril decreased peripheral BP to normal and by the same extent. Although both drugs lowered the carotid AI, the response to atenolol was significantly smaller than that to fosinopril, resulting in a trend toward a persistently higher AI compared with the normotensive subjects. Results observed in those in whom the antihypertensive agent was used as monotherapy were similar to results in those in whom the diuretic had been added. In these subgroups the AI resulting after atenolol treatment was significantly higher than in the normotensive subjects. This more beneficial action of the ACE inhibitor than the β-blocker on wave reflection is similar but not identical to the short-term actions of these types of drugs described above in which the β-blocker actually exacerbated wave reflections rather than decreasing them to normal levels.

Bar graph shows 24-hour ambulatory heart rate in normotensive subjects (N) and hypertensive patients before and after 8 weeks of treatment with fosinopril or atenolol. Solid and open bars represent those hypertensive patients who received both diuretics and the drug; cross-hatched and vertically hatched bars represent those hypertensive patients who did not receive diuretics.

Bar graphs show 24-hour ambulatory systolic and diastolic pressures in normotensive subjects (N) and hypertensive patients before and after 8 weeks of treatment with fosinopril or atenolol. Bars are as defined in Fig 8⇑ legend.

Bar graph shows carotid artery augmentation index in normotensive subjects (N) and hypertensive patients before and after 8 weeks of treatment with fosinopril (F) or atenolol. Bars are as defined in Fig 8⇑ legend.

Discussion

The main findings of this series of studies are the following: (1) There are distinct hemodynamic alterations associated with essential hypertension whose details can be elucidated with invasive measurements. (2) The various classes of antihypertensive agents affect these hemodynamic alterations differently; only a nonspecific smooth muscle vasodilator (nitroprusside) and a calcium antagonist (nifedipine) completely normalized all the hemodynamic alterations after short-term administration. β-Blockade actually appeared to be deleterious. (3) The more beneficial action of an ACE inhibitor compared with a β-blocker appeared to be maintained during 8 weeks of administration whether or not a diuretic was added. (4) New noninvasive techniques such as applanation tonometry might be useful for assessing the effects of, for instance, wave reflections.

The similarity of the baseline alterations among the several different groups of hypertensive patients, which were studied over a period of several years, helps confirm that these distinct alterations are indeed a hallmark of this young, essential hypertensive population. Some of these findings have been reported in previous studies,344546 but to our knowledge this combined group comprises the largest and most homogeneous group of essential hypertensive patients in which such detailed measurements have been made.

For many reasons it is perhaps not surprising to find a disparity of action of these drugs. First, the predominant modes of actions of these various antihypertensive agents differ. Second, the actions of each drug may not necessarily be limited to a single system.14474849 Third, a particular class of drug, for example, a calcium channel antagonist, may have variable actions in the arterial tree.50 There is some evidence that the hemodynamic parameters we measured may represent predominant contributions from different regions of the arterial system (eg, compliance from the proximal aorta,51 wave reflections from near the renal and aortic bifurcations,5253 and resistance from the periphery54 ). Our long-term data also indicate that the different beneficial effects on reducing central wave reflections of β-blockade and ACE inhibition were not manifested by any difference between the drugs in their effects on peripheral BP. Similar observations with other vasodilators have been reported.55565758 Clearly, more detailed regional measurements are needed to delineate the specific regional effects of the various drug classes.

The parallelism between the results of our short- and long-term observations on the effects of β-blockade and calcium antagonism on wave reflections (β-blockade was deleterious in the short term and less beneficial in the long term) is encouraging. These results suggest that at least under some conditions long-term effects might be predictable from short-term responses. If these results can be generalized, the data suggest that a calcium channel blocker might be the optimal drug for normalizing hemodynamics; this is supported by studies showing a beneficial effect of long-term calcium channel blockade on vessel compliance and other hemodynamic parameters.575859606162 The beneficial effects of calcium antagonism are consistent with the observation that nitroprusside completely normalized hemodynamics.163 Since both of these agents act directly at a common denominator, namely, the vascular smooth muscle, the results suggest that at least at this young age the hemodynamic alterations are related to reversible, excessive levels of smooth muscle tone in the arterial system; however, the specific mechanisms still need to be resolved.

One reason for the deleterious action of the β-blocker may be that it unmasks a degree of α-adrenergically mediated vasoconstriction because some of its deleterious effects are reversed when an α-blocker is added to β-blockade. Similar effects have been observed in other studies.456465 How much this short-term effect is ameliorated over time is unclear, but our data suggest that not all of it is. Other possible reasons relate to the heart rate–lowering effect of β-blockers. This may be deleterious from two standpoints. First, because of the steep fall of the impedance modulus curve in the low-frequency range, lowering heart rate, that is, the fundamental frequency, causes the heart and arterial system to interact less efficiently, in that more energy is expended in producing pulsations. Second, slowing heart rate provides an opportunity for the reflected wave (if the pulse wave velocity is unchanged) to appear in late systole rather than in diastole, thereby increasing the AI.

Both the short- and long-term ACE inhibitor results show only a partial normalization of wave reflections. Although this could be due to the fact that abnormalities of this system are not the sole or predominant mechanism for essential hypertension, there is another possibility. The fact that both indexes were only partially normalized suggests that there may be an upper limit of potential hemodynamic benefit obtainable from this type of agent. Likewise, α-adrenergically mediated tone is probably not the complete explanation for the hemodynamic alterations because arterial compliance was not completely normalized after α-blockade. In fact, examination of compliance at other pressures clearly indicated that α-blockade by itself or with β-blockade did not normalize compliance (data not shown).

Some limitations to our results deserve comment. First, all of our short-term studies were performed after premedication with chlorpheniramine. How and whether this drug affects hemodynamic responses differently in normotensive subjects or hypertensive patients is not known but deserves examination. Second, even though our long-term data indicate that the combination of an ACE inhibitor or β-blocker with a thiazide diuretic results in the same hemodynamic responses as those drugs without the added diuretic, these results do not directly address the issue of the direct effect of a diuretic alone on the hemodynamic responses such as aortic impedance, wave reflections, and compliance. Since thiazide diuretics may have some effect on the renin-angiotensin system, it would be useful to have such information. To our knowledge, this is not available.

Although noninvasive techniques probably will never be able to describe hemodynamics in as detailed a fashion as invasive techniques, they may play an increasingly important role for the examination of certain aspects of function such as wave reflection. For example, in recent years applanation tonometry has received wide attention, and several studies seem to suggest that it is a reasonably reliable method for noninvasively indexing the results of wave reflections.333435 Even though the AI is an indirect and the wave reflection index is a direct measure of the extent of wave reflections, both responded in the same manner to the various drugs. This indicates that the AI, whether recorded invasively from the aortic pressure trace or noninvasively from the carotid artery, is a reasonably accurate indicator of the amount of reflection in the arterial system. There are still clear limitations to this technique, such as the problematic issue of absolutely quantifying BP, that must be kept in mind. As other techniques for noninvasive estimation of central aortic pressures, flows, and anatomy become available,5766 the goal of being able to noninvasively yet adequately assess the arterial system for purposes such as those described here nears reality.

Acknowledgments

This work was supported in part by grant DOH 84-HR-204 from the Department of Health, the Executive Yuan of the Republic of China.